Preclinical Characterization of RSM-932A, a Novel Anticancer Drug Targeting the Human Choline Kinase Alpha, an Enzyme Involved in Increased Lipid Metabolism of Cancer Cells

Lacal, Juan Carlos; Campos, Joaquı́n M.

doi:10.1158/1535-7163.mct-14-0531

Cited by 55 publications

(59 citation statements)

References 47 publications

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“…Consistently, pharmacological inhibitors of CHKA has also displayed antiproliferative, proapoptotic and antitumoral effects against multiple tumor-derived cancer cells as well as tumor xenografts [18, 23, 32, 43–46]. Indeed, one CHKA inhibitor, designated as TCD-717 or RSM-932A, has recently completed Phase I clinical trials for the treatment of advanced solid tumors (ClinicalTrial.gov Identifier: NCT01215864) [27]. Thus, together our findings with what has been reported so far, inhibition of CHKA may have a broad spectrum application as an attractive novel anticancer strategy.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

Wang

Cai

et al. 2016

Oncotarget

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Aberrant expression of choline kinase alpha (CHKA) has been reported in a variety of human malignancies including colorectal carcinoma (CRC). However, the role of CHKA in the progression and prognosis of CRC remains unknown. In this study, we found that CHKA was frequently upregulated in CRC clinical samples and CRC-derived cell lines and was significantly correlated with lymph node metastasis (p = 0.028), TNM stage (p = 0.009), disease recurrence (p = 0.004) and death (p < 0.001). Survival analyses indicated that patients with higher CHKA expression had a significantly shorter disease-free survival (DFS) and disease-specific survival (DSS) than those with lower CHKA expression. Multivariate analyses confirmed that increased CHKA expression was an independent unfavorable prognostic factor for CRC patients. In addition, combination of CHKA with TNM stage was a more powerful predictor of poor prognosis than either parameter alone. Functional study demonstrated that knockdown of CHKA expression profoundly suppressed the growth and metastasis of CRC cells both in vitro and in vivo. Mechanistic investigation revealed that EGFR/PI3K/AKT pathway was essential for mediating CHKA function. In conclusion, our results provide the first evidence that CHKA contributes to tumor progression and metastasis and may serve as a novel prognostic biomarker and potential therapeutic target in CRC.

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Section: Discussionmentioning

confidence: 99%

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

Wang

Cai

et al. 2016

Oncotarget

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“…Besides its regular function (19), CHKA was reported to be important in cancer carcinogenesis and development (8,20). Granata et al reported that CHKA could act as a potential druggable target for ovarian cancer by regulating cell aggressiveness and drug sensitivity (21).…”

Section: Discussionmentioning

confidence: 99%

CHKA mediates the poor prognosis of lung adenocarcinoma and acts as a prognostic indicator

et al. 2016

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Choline kinase α (CHKA), the enzyme that converts choline to phosphocholine, has been studied in human carcinogenesis widely. However, the expression and underlying clinicopathological characteristics of CHKA in lung adenocarcinoma remains elusive. In the present study, a tissue microarray of 119 pairs of lung adenocarcinoma samples and corresponding adjacent normal mucosae was used to analysis CHKA expression by immunohistochemistry, and CHKA was observed to exhibit enhanced expression in lung adenocarcinoma tissues. Elevated CHKA expression in lung adenocarcinoma tissues at the gene and protein level was observed. The levels of CHKA expression were closely associated with the poor prognosis status of lung adenocarcinoma patients. Furthermore, certain clinicopathological characteristics such as tumor diameter and differentiation were observed to be significant in those lung adenocarcinoma patients who displayed enhanced CHKA expression. The analysis of CHKA expression could provide a more precise way to predict the prognosis of lung adenocarcinoma patients. Collectively, the present study revealed a novel biomarker in lung adenocarcinoma, and indicated that CHKA may be a promising prognostic marker and therapeutic target for lung adenocarcinoma.

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“…Lacal and colleagues have tested several groups of compounds that inhibit ChKα activity, some of which displayed significant levels of antiproliferative activity and led to a reduction of tumor growth (65–67). One of these inhibitors, TCD-717 (68), is currently being tested in a phase I clinical trial (). Bhujwalla and colleagues have developed siRNA and shRNA strategies (Figure 3) (69, 70), and siRNA-based nanoparticles against ChKα (71) for anticancer therapy.…”

Section: Choline Kinase αmentioning

confidence: 99%

Targeting Phospholipid Metabolism in Cancer

2016

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All cancers tested so far display abnormal choline and ethanolamine phospholipid metabolism, which has been detected with numerous magnetic resonance spectroscopy (MRS) approaches in cells, animal models of cancer, as well as the tumors of cancer patients. Since the discovery of this metabolic hallmark of cancer, many studies have been performed to elucidate the molecular origins of deregulated choline metabolism, to identify targets for cancer treatment, and to develop MRS approaches that detect choline and ethanolamine compounds for clinical use in diagnosis and treatment monitoring. Several enzymes in choline, and recently also ethanolamine, phospholipid metabolism have been identified, and their evaluation has shown that they are involved in carcinogenesis and tumor progression. Several already established enzymes as well as a number of emerging enzymes in phospholipid metabolism can be used as treatment targets for anticancer therapy, either alone or in combination with other chemotherapeutic approaches. This review summarizes the current knowledge of established and relatively novel targets in phospholipid metabolism of cancer, covering choline kinase α, phosphatidylcholine-specific phospholipase D1, phosphatidylcholine-specific phospholipase C, sphingomyelinases, choline transporters, glycerophosphodiesterases, phosphatidylethanolamine N-methyltransferase, and ethanolamine kinase. These enzymes are discussed in terms of their roles in oncogenic transformation, tumor progression, and crucial cancer cell properties such as fast proliferation, migration, and invasion. Their potential as treatment targets are evaluated based on the current literature.

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Preclinical Characterization of RSM-932A, a Novel Anticancer Drug Targeting the Human Choline Kinase Alpha, an Enzyme Involved in Increased Lipid Metabolism of Cancer Cells

Cited by 55 publications

References 47 publications

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

CHKA mediates the poor prognosis of lung adenocarcinoma and acts as a prognostic indicator

Targeting Phospholipid Metabolism in Cancer

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